Pharmaceutical compositions containing Bulbophyllum

ABSTRACT

Described are pharmaceutical compositions containing Bulbophyllum, in particular compositions containing  Bulbophyllum neilgherese,  optionally in combination with suitable pharmaceutical excipients and carriers, as well as their use for treating illnesses, in particular illnesses of the cardio-vascular system.

The present invention relates to pharmaceutical compositions containingBulbophyllum, particularly Bulbophyllum neilgherense, and its use fortreating illnesses, in particular illnesses of the cardio-vascularsystem.

There is a considerable need for the development of drugs andmedicaments, respectively, having good effectiveness and largeindication indexes as well as little or no side effects, to augment thepresent therapies of cardio-vascular illnesses.

Surprisingly, this object could be successfully achieved by providingthe pharmaceutical compositions containing Bulbophyllum described below.

U.S. Pat. No. 4,691,472 relates to the cultivation of Epiphytes,especially orchids. Bulbophyllum is stated as one example of an orchidgenus.

So far, Bulbophyllum extracts have only been disclosed in EP-0 627 213.Here, a cosmetic formulation for the promotion of hair growth isdescribed, said formulation containing an extract from orchid plants,i.a. Bulbophyllum.

In the light of this state of the art, it was completely unexpected todiscover that the plant species Bulbophyllum shows the pharmacologicaleffects described below, making it especially useful for the treatmentof cardio-vascular diseases.

The following description illustrates in detail the pharmacological testresults which led to the above conclusions, as well as specificcardio-vascular indications.

Bulbophyllum neilgherense is a member of the orchidaceae family. It isan epiphyte that grows on broadleaf trees, more specifically on tallerrain forest trees. The rhizome is thick and of creeping growth. Thepseudo-bulb is 3–5×2–2.5 cm, conicalovate, tapering off in a solitaryleaf. This leaf is 4–11×1.8–2.2 cm, elliptically-oblonged, narrowed atits base. The flowers are brown, sometimes with a purple shade, andreside in a panicle 7–12 cm long, emanating from the pseudo-bulb's base.The peduncles are 3–4 mm long. The spatheceous bract of theinflorescence is 5–6 mm long, inverted lanceolate. The dorsal sepals are4–5 mm long, ovate and concave. The lateral sepals are 7–8 cm long, ofscimitar-shape, their accreted inner rims forming a concave, cymbiformstructure. The petals are 3–3.5 mm long, triangular-ovate. The flowerlips are 5–6 mm long, reddish, three-lobed; the middle lobe is prolongedand ovate-lanceolate, the lateral lobes are linear. There are 4 anthersof waxen appearance. The plant is common all over South-West India.

For the drugs according to the present invention predominantly the mainpart of the plant is used, i.e. the entire bulb without the appendingroots and without protruding leaf.

In this description, the term drugs refers to dried or otherwiseprocessed parts of plants (herbal drugs) which are used for medicalpreparations. Furthermore, it includes certain raw products extractedfrom these plants (e.g. fatty and ethereal oils, resins, balsams andgums).

Drug preparations which comprise an accumulation of active substancesinclude, but are not limited to: extracts, paints, percolates,mazerates, infusions, pressed juices, decoctions (tea), distillates.Drug ingredients refers to the sum of chemical components thatcharacterize a drug, i.e. therapeutically active substances as well asaccompanying or inert substances without innate therapeutical action,such as cellulose, starch, waxes. The latter usually make for the bulkof extra substances.

The plant that is useful for the preparation of drugs can be harvestedfrom its natural habitat, or artificially grafted onto other trees, orgrown in green houses.

When working up the plant, conventional techniques can be employed, e.g.purification, milling and drying, as well as stabilization processes.One preferred example of drying techniques is lyophilization.

Due to the fact that neither the plant itself nor the drug deteriorateduring long time transports or under the exposure of tropical heat,freeze-drying and processing can be postponed.

The pharmaceutical composition or the drug, respectively, can beprepared in various ways using common techniques, but preferably astriturations with milk sugar or alcoholic extracts. When prepared asalcoholic extracts, the alcohol content by volume is 80 to 100%,preferably 94 to 98%, even more preferred 96%.

The drug content of said extract or said trituration per single dose ispreferably 1 ng to 1 mg, even more preferred 10 ng to 1 mg.

Preferably, the drug is administered as 1 to 3 daily doses over a periodof 1 to 12 months, preferably 2 to 5 months, more preferred 3 to 4months. Alternatively, the administration of single doses with intervalsof 1 day to 12 months, more preferred 3 to 4 months, can be sufficientto achieve the desired effect according to the present invention.

A person skilled in the art will be able to determine and appropriatelyadjust the adequate dosage for achieving the optimum therapeutic effect.

Pharmaceutical Administration Forms

Pharmaceutical compositions containing Bulbophyllum according to thepresent invention are prepared and administered according toconventional methods using common pharmaceutical technologies.

For this purpose, the drug, or preferably its extraction or trituration,is processed together with suitable pharmaceutically acceptableexcipients and carriers to prepare drug forms that can be used forvarious indications and application sites.

One important systemic form of application is the peroral application oftablets, hard or soft gelatine capsules, dragées, powders, pellets,micro capsules, oblonged comprimates, granulae, chewing tablets, suckingtablets, chewing gums, sachets, or globuli.

Excipients that are used for the preparation of perorally administeredpharmaceutical compositions are e.g. antiadhesives, lubricants andanticaking agents, dispersants, such as flame hydrolyzed dispersesilica, disintegrants, such as various types of starches, PVP, celluloseesters acting as granulating agents, such as ceraceous and/or polymericsubstances on the basis of Euthragit™, cellulose or Cremophor™.

Other ingredients that can be used are antioxidants, sweetening agents,such as saccharose, xylitol or mannite, taste corrigents, flavors,preservatives, colorants, buffers, direct application vehicles, such asmicrocrystalline cellulose, starch and hydrolyzed starch (e.g.Celutab™), milk sugar, polyethylene glycol, polyvinyl pyrrolidone anddicalcium phosphate, lubricants, fillers, such as lactose and starch,binders consisting of lactose, certain kinds of starch, e.g. wheat, cornor rice starch, cellulose derivatives, such as methyl cellulose,hydroxypropyl cellulose or siliceous earth, talcum, stearates, such asmagnesium stearate, aluminium stearate, calcium stearate, talc,siliconized talc, stearic acid, cetyl alcohol, hydrogenated fats.

Examples of common skin application forms are the conventionalemulsions, gels, ointments, creams, or mixed phase or amphiphilicemulsion systems (oil-in-water/water-in-oil mixed phases), as well asliposomes and transferosomes. Their epidural application is alsopreferred.

Examples for suitable excipients or carriers are sodium alginate thatacts as gel forming agent for the preparation of an appropriate base, orcellulose derivatives, such as guar or xanthan gum, anorganic gelforming agents, such as aluminium hydroxide or bentonite (so-calledthixotropic gel forming agents), polyacrylic acid derivatives, such asCarbopol™, polyvinyl pyrrolidone, microcrystalline cellulose orcarboxymethyl cellulose. Amphiphilic compounds of low or high molecularweight, such as phospholipids, can also be taken into consideration.These gels can exist as water-based hydrogels or as hydrophobicorganogels, e.g. on the basis of admixtures of paraffin hydrocarbons oflow or high molecular weight and vaseline.

Suitable emulsifiers that can be used for the preparation ofoil-in-water or water-in-oil emulsions are anionic, cationic or neutralsurfactants, such as alkaline soaps, metal soaps, amino soaps,sulfurized and sulfonized compounds, invert soaps, high fatty alcohols,partial esters of sorbitan or polyoxyethylene sorbitan fatty acids, woolwax, lanolin, among other synthetic products.

Hydrophilic organogels can e.g. be prepared on the basis of polyethyleneglycol of high molecular weight. These gel-like forms can be washed off.Lipids consisting of fatty and/or oily and/or waxy components useful forthe preparation of ointments, creams or emulsions are e.g. vaseline,natural or synthetic waxes, fatty acids, fatty alcohols, fatty acidesters, such as mono-, di-, or triglycerides, paraffin oil or vegetableoil, hydrogenated castor oil or coconut oil, lard, synthetic fats, e.g.on the basis of caprylic acid, capric acid, lauric acid and stearicacid, or mixtures of triglycerids, such as Miglycol™.

For pH adjustments, osmotically active acids and alkalis can be used,such as hydrochloric acid, citric acid, sodium hydroxide solutions,potassium hydroxide solutions, sodium hydrogen carbonate, as well asbuffer systems, such as citrate, phosphate, tris-buffers or triethanolamine.

Furthermore, preservatives, such as methyl or propyl benzoate(parabene), or sorbic acids can be added to enhance stability.

Other examples for topic application forms are pastes, powders orsolutions. The pastes often contain very high solid lyophilic andhydrophilic excipients that serve as bases for providing consistency.For the improvement of dispersity, fluidity and glide-ability, as wellas for agglomerate prevention, the dustable or topically applicablepowders can contain e.g. various types of starches, such as wheat orrice starch, flame hydrolyzed disperse silica or silaceous earths thatcan also serve as dilutants.

Preferred transdermal systems that are able to controllably release theactive substances over short or prolonged periods of time are plasterpreparations consisting of several layers and/or mixtures of suitableexcipients and carriers. To enhance or accelerate penetration, varioussubstances can be added during the preparation of said transdermalsystems in order to promote membrane permeation, e.g. permeationpromotors, such as oleic acid, Arzone™, adipic acid derivatives,ethanol, urea, propyl glycol, as well as suitable excipients andcarriers, such as solvents, polymeric components, e.g. on the basis ofEuthragit™.

The plasters are preferably applicated in the precordial area.

A further administration method uses injectables. They are preparedeither as ampoules or so-called ready-to-use injectables, such assyrettes or disposable syringes, and also punctable containers formultiple withdrawals. Said injectables can be applied subcutaneous(s.c.), intramuscular (i.m.), intravenous (i.v.), or intracutaneous(i.c.). The specific convenient injection form can be prepared assolutions, suspensions of crystals, or nanoparticulate orcollidal-diperse systems, such as hydrosols.

The injectables can also be prepared in the form of concentrates, whoseactive substance content can be adjusted using water-based isotonicdilutants. Furthermore, they can be prepared as powders, such aslyophylisates, that are only solved or dispersed immediately beforeapplication.

Excipients and carriers that can be used for injectable preparations aresterilized water, pH controlling substances, such as organic andinorganic acids and alkalis as well as their salts, buffers foradjusting the pH value, isotonicity agents, such as sodium chloride,sodium hydrogen chloride, glucose and fructose, surfactants orsurface-active substances, respectively, and emulsifiers, such aspartial fatty acid esters of polyoxyethylene sorbitan (Tween™) or fattyacid esters of polyoxyethylene (Cremophor™), fatty oils, such asgroundnut oil, soy bean oil and castor oil, synthetic fatty acidsesters, such as ethyl oleate, isopropyl myristate and neutral oil(Miglycol™) as well as polymeric excipients, such as gelatine, dextrane,polyvinyl pyrrolidone, solubility increasing additives consisting oforganic solvents, such as propylene glycol, ethanol, N,N-dimethylacetamide, propylene glycol or complex forming substances, such ascitrates and urea, preservatives, such as the hydroxy propyl and methylesters of benzoic acid, benzyl alcohol, antioxidants, such as sodiumsulfite, and stabilizing agents, such as EDTA.

The drugs can also be administered perlingually.

Delayed release administration forms can also be applied.

A person skilled in the art will readily be able to identify and preparethe adequate drug forms in accordance with prescriptions and processingmethods on the basis of pharmaceutical/physical knowledge.

Indication Areas

The pharmaceutical composition containing Bulbophyllum according to thepresent invention is useful for treating all disorders of thecardio-vascular system, especially in case of cardiopathy in familyhistory, unusual perception of the heart, cardiac condition relatedanxiety, chest tightness, chest pressure, bradycardia, tachycardia,extrasystoles, arrhythmia, palpitation, atrial fibrillation, cardialgia,stabbing heart pains, sternum pains, heart pains radiating into the leftarm and tingling sensation in the left arm, angina pectoris, stenosis ofthe coronary arteries, myocardial infarct, cardiac insufficiencyinvolving edemas, myocardial and septal hypertrophy, right ventriclecardiomegaly, ventricle septum defect, atrium septum defect, primarypulmonary hypertension, hypertonia, peripheral acral cyanosis, lipcyanosis, dyspnea, exertional dyspnea, altitude intolerance, coronariarelated hot flushes, disturbed blood flow in the limbs caused by heartinsufficiency, cold limbs, physical weakness caused by heartinsufficiency, reduced ability, weak condition following rheumaticfever, valvular disorders, cardiopathic difficulties falling asleep,insomnia, cardiopathic cough.

Pharmacological Test Section

In the course of 3 years, 127 patients were treated with thepharmaceutical composition according to the present invention. 61 ofthese patients were women (49%). Among these 127 patients, 82individuals recovered to a considerable extent or even completely. Amongthese 82 patients, 31 individuals experienced a resounding subjectivelyand objectively observed recovery.

Each of said 127 patients was given one single dose. During theeffective period of said single dose no other medicaments wereadministered, as well as no vitamins, trace elements, minerals,physiotherapeutics etc.

For said 82 patients who had recovered considerably or completely, thesingle dose administration had to be repeated only after 7 weeks. Thelongest duration of effect was 11 months, i.e. only after 11 months didthese patients experience the recurrency of ailments that requiredanother dose. The average duration of effect of a single dose was threeto four months. This single dose duration of effect varies with theseverity of the disorder.

Comparison with Other Heart Therapeutics in Terms of Potence,Side-Effects, Duration and Cost Effectiveness

When compared to the pharmaceutical composition containing Bulbophyllumaccording to the present invention, no other heart therapeutic possessesa similar indication index and activity range.

Due to the fact that the administration is done in a doctor's practiceand no subsequent administration is necessary until the recurrence ofthe patient's ailments, no other heart therapeutic has a compliance ashigh as the pharmaceutical compositions containing Bulbophyllumaccording to the present invention.

Most patients recovered without a preceding aggravation of symptoms.Approximately 5% of the group experienced a mild aggravation that lastedno longer than three to five days. Approximately 15% of the groupexperienced a short-term aggravation of symptoms emerging during thethird week after administration, after a few hours or a few days withoutfurther administration, however, the symptoms had eased.

None of the examinated patients developed any side-effects.

No other heart therapeutic has such long duration of effect.

Furthermore, the cost of treatment with the extract according to thepresent invention is only ⅙ of conventional heart therapeutics, e.g.Niphedipin (Adalat).

Due to the fact that most patients suffering from heart disease aremultimorbid, the costs for treating their ailments with additionaltherapeutics would have to be added in case of conventional therapieswith state of the art drugs. In case of the Bulbophyllum therapy, noother medicament was administered to the patient. Consequently, thecosts for other therapeutics are eliminated, which leads to a stillbetter performance of Bulbophyllum in terms of cost effectiveness.

1. A pharmaceutical composition containing Bulbophyllum neilgherense andmilk sugar, optionally in combination with pharmaceutical acceptableexcipients and/or carriers; wherein said composition is in the form of atrituration.
 2. The pharmaceutical composition according to claim 1,wherein the Bulbophyllum neilgherense content per single dose is in therange of 1 ng to 1 mg.
 3. The pharmaceutical composition according toclaim 1, wherein the trituration is processed into a form for epidural,peroral or topical administration.
 4. The pharmaceutical compositionaccording to claim 1, wherein the trituration is processed into a formfor injectable administration.
 5. The pharmaceutical compositionaccording to claim 1, for the treatment of cardiovascular disorders. 6.A pharmaceutical composition for treating cardiovascular disorderscomprising an effective amount of Bulbophyllum neilgherense and milksugar in combination with pharmaceutically acceptable excipients and/orcarriers.